PKs are enzymes that catalyze the phosphorylation of hydroxy groups on tyrosine, serine, and threonine residues of proteins. The consequences of this seemingly simple activity are staggering: cell growth, differentiation, and proliferation, i.e., virtually all aspects of cell life in one way or another, depend on PK activity. Furthermore, abnormal PK activity has been related to a host of disorders, ranging from relatively non-life threatening diseases such as psoriasis to extremely virulent diseases such as glioblastoma (brain cancer). The PKs can be conveniently broken down into two classes, the protein tyrosine kinases (PTKs) and the serine-threonine kinases (STKs).
One of the prime aspects of PTK activity is their involvement with growth factor receptors. Growth factor receptors are cell-surface proteins. When bound by a growth factor ligand, growth factor receptors are converted to an active form, which interacts with proteins on the inner surface of a cell membrane. This leads to phosphorylation on tyrosine residues of the receptor and other proteins and to the formation inside the cell of complexes with a variety of cytoplasmic signaling molecules that, in turn, effect numerous cellular responses such as cell division (proliferation), cell differentiation, cell growth, expression of metabolic effects to the extracellular microenvironment, etc.
Small molecules that act as PK inhibitors have been identified and include, for example, 3-pyrrole substituted 2-indolinone compounds as disclosed in PCT International Publication No. WO 01/60814 (Tang et al.). 3-Pyrrole substituted 2-indolinone compounds include, for example, N-[2-(diethylamino)ethyl]-5-[(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide as disclosed in PCT International Publication No. WO 01/60814 (Tang et al.). However, the disclosure is silent as to the preparation of and the nature of specific crystal forms of salts of N-[2-(diethylamino)ethyl]-5-[(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide. There exists a need for crystalline forms of such materials that have superior chemical and/or physical properties that are useful in drug delivery applications.